Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome

Abstract

Purpose: Patients with Lynch syndrome (LS) have a significantly increased risk of developing upper-tract urothelial carcinoma (UTUC). Here, we sought to identify differences in the patterns of mutational changes in LS-associated versus sporadic UTUCs.

Patients and methods: We performed targeted sequencing of 17 UTUCs from patients with documented LS-associated germline mutations (LS-UTUCs) using the Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets targeted exon capture assay and compared the results with those from a recently characterized cohort of 82 patients with sporadic UTUC.

Results: Patients with LS-UTUC were significantly younger, had had less exposure to tobacco, and more often presented with a ureteral primary site compared with patients with sporadic UTUC. The median number of mutations per tumor was significantly greater in LS-UTUC tumors than in tumors from the sporadic cohort (58; interquartile range [IQR], 47-101 v 6; IQR, 4-10; P < .001), as was the MSIsensor score (median, 25.1; IQR, 17.9-31.2 v 0.03; IQR, 0-0.44; P < .001). Differences in the genetic landscape were observed between sporadic and LS-associated tumors. Alterations in KMT2D, CREBBP, or ARID1A or in DNA damage response and repair genes were present at a significantly higher frequency in LS-UTUC. CIC, NOTCH1, NOTCH3, RB1, and CDKN1B alterations were almost exclusive to LS-UTUC. Although FGFR3 mutations were identified in both cohorts, the R248C hotspot mutation was highly enriched in LS-UTUC.

Conclusion: LSand sporadic UTUCs have overlapping but distinct genetic signatures. LS-UTUC is associated with hypermutation and a significantly higher prevalence of FGFR3 R248C mutation. Prospective molecular characterization of patients to identify those with LS-UTUC may help guide treatment.

Fig 1.

(A) Oncoprint of germline and somatic mutations in mismatch repair (MMR) genes and in POLE in the Lynch cohort. (B) Mutational decomposition analysis of the samples with ≥ 10 somatic mutations. (*) Hypermutated sporadic upper-tract urothelial carcinoma (UTUC) tumor with a hotspot mutation in POLE. (C) Microsatellite instability (MSI) sensor scores across the two cohorts. (D) Frequency of somatic alterations in Lynch syndrome–associated (n = 17) and sporadic UTUC (n = 82) cohorts. AID/APOBEC, activation-induced cytidine deaminase/apolipoprotein B mRNA-editing enzyme catalytic polypeptide; CNV, copy-number variation; DDR, DNA damage repair; NS, non significant; RCC, renal cell carcinoma.

Fig 2.

(A) Number of somatic alterations in Lynch syndrome–associated upper-tract urothelial carcinoma (LS-UTUC) and sporadic UTUC tumors and their association with FGFR3 mutation status. (B) Total mutation count in patients with somatic FGFR3 R248C and FGFR3 S249C mutations.

Fig 3.

Flow chart of identification of the patients with FGFR3 R248C mutation in the clinical Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets (MSK-IMPACT) cohort. LS, Lynch syndrome; SCC, squamous cell carconima; UC, urothelial carcinoma; UCB, UC of the bladder; UTUC, upper tract UC.

Fig A1.

FACETS analysis of five samples without somatic alterations corresponding to germline mutations identified in mismatch repair genes. Sample s_BB_lynch_019_T was found to present loss of heterozygosity in MSH2.

Fig A2.

Oncoprint of the most frequent genes altered in the Lynch cohort.

Fig A3.

Lollipop plots of FGFR3 mutations in the sporadic and Lynch cohorts.